Poxviruses are dermatotrophic DNA viruses that cause human diseases ranging in severity from a mild local skin infection (molluscum contagiosum) to a catastrophic systemic illness signaled by a generalized pustular rash (smallpox). Understanding poxvirus pathogenesis, particularly its interaction with skin immune system, and the development of skin directed antipoxvirus drug therapy are important issues. The current available therapeutics for human poxvirus infections are quite limited and non-specific. This proposal details a 5-year training program for the development of an academic career in investigative dermatology, poxvirology and immunology. Having completed clinical training in dermatology and a research fellowship in poxvirology, the Principal Investigator (PI) will use this dedicated period to acquire the knowledge and skills necessary to become an independent researcher. The PI will be mentored by a leading poxvirologist and biochemist, Dr. Stewart Shuman, and an esteemed immunologist, Dr. Alan Houghton to explore the interface of poxvirus with skin immune system and to develop novel anti-poxvirus drugs. The Memorial Sloan-Kettering Cancer Center will provide institutional support. Ample resources and multiple career developmental activities will be available to help the PI to achieve her goals. The specific aims of the proposal are to (i) Use genetically modified vaccinia virus to dissect how vaccinia virus intersects TLR signaling, and the NF-?B and IFN pathways in LCs/DCs;Determine the molecular targets for antipoxvirus drug(s);(ii) Evaluate the immunological responses of human monocyte-derived DCs (moDCs) and plasmacytoid DCs (pDCs) to vaccinia virus infection;(iii) Establish a skin infection model in immunocompromised mice;Test the efficacy of topical application of antipoxvirus drugs. This study is expected to generate new knowledge and insights into how skin immune system responds to poxvirus infection and how poxvirus intersects key signaling pathways to achieve immune evasion. It will also allow us to develop novel antipoxvirus drugs and test them in an in vivo mouse skin model.